PROJECT SUMMARY Perivascular spaces are an emerging marker of cerebral small vessel disease often seen as fluid-filled spaces on magnetic resonance imaging (MRI) in older adults. The purpose of this proposal is to better understand the underlying etiology and clinical consequences of perivascular spaces. In particular, we will assess if age- related arterial stiffening drives higher blood pulsatility in perforating arteries of the basal ganglia, increasing force transmission to surrounding tissue, and leading to morphological change in the form of enlarged perivascular spaces. We propose to apply aortic pulse wave velocity, a gold-standard marker of arterial stiffening, to test whether increased pulsatility is associated with longitudinal perivascular space burden in the basal ganglia. Next, we will examine associations between baseline perivascular space burden and longitudinal cognitive trajectory. The basal ganglia has been implicated in executive function and information processing speed mediated by frontal-subcortical networks. Therefore, perivascular spaces in the basal ganglia may result in worse cognitive outcomes in these particular domains. Apolipoprotein E (APOE)-?4 is the strongest genetic susceptibility risk factor for sporadic Alzheimer?s disease and a moderator of vascular damage. Given our prior work suggesting arterial stiffness interacts with APOE-?4 on brain health outcomes, we will also assess APOE-?4 as an effect modifier. To fulfill the research aims of this F31 application, we will leverage exceptional resources from the Vanderbilt Memory & Alzheimer?s Center, Vanderbilt Memory & Aging Project, Vanderbilt University Institute of Imaging Science, Vanderbilt Translational Clinical Cardiovascular Research Group, Vanderbilt Advanced Computing Center for Research and Education, and the Vanderbilt Brain Institute. The candidate, Corey Bown, will carry out the proposed research with the support of an interdisciplinary mentorship team, including international experts in the neurobiology of Alzheimer?s disease and small vessel disease, geriatric neuropsychology, neuroscience, cardiac and brain MRI, computational genetics, and perivascular space anatomy and physiology. The parallel training plan will provide the candidate with the necessary knowledge and skillset to complete the proposed research aims and develop into a successful neuroscientist working at the neurobiological intersection of small vessel disease and Alzheimer?s disease. Results from this research will offer crucial information about the etiology and clinical consequences of perivascular spaces to inform future prevention and therapeutic efforts.